Update on the management of STEMI Elliot Rapaport, M.D. San Francisco, CA December 14, 2007
Universal MI Definition Committee 2007 Recommendations Type 1 Spontaneous MI associated with ischemia and due to a primary coronary event such as plaque erosion, rupture, fissuring, or dissection. Type 2 Due to an imbalance between supply and demand of oxygen. Result of ischemia but not ischemia from thrombosis of coronary artery. Type 3 Sudden cardiac death, including cardiac arrest, with symptoms of ischemia, accompanied by new ST elevation or LBBB. Verified coronary thrombus by angiography or autopsy but death occurring before blood samples could be obtained or before biomarkers appear in the blood Type 4 MI associated with PCI. PCI-related increase of biomarkers (assuming a normal troponin baseline) greater than 3X 99 th percentile of the upper reference limit is by convention defined as MI. Type 4b-MI associated with verified stent thrombosis via angiography or autopsy. Type 5 MI associated with CABG (> 5X 99 th percentile upper reference) limit plus new Q waves or LBBB or imaging evidence of new loss.
Primary PCI vs Thrombolysis in STEMI: Meta-analysis 25 20 Short-term Outcomes P<.0001 23 Randomized Clinical Trials N = 7739 Frequency (%) 15 10 P=.0002 P<.0001 P=.032 P<.0001 PTCA Thrombolytic therapy 5 P<.0001 0 Death Nonfatal MI Recurrent Ischemia Hemorrhagic Stroke Major Bleed Death, Nonfatal Reinfarction, or Stroke Note: When primary PCI is compared to alteplase and the SHOCK trial is excluded, mortality is 5.5% v 6.7%, p=0.081 STRIVE TM
PG.Steg 0105 NRMI-2: Primary PCI door-to-balloon time vs mortality 10 N=27,080 P<0.00001 Mortality (%) 8 6 4 4.2 4.6 5.1 6.7 8.5 7.9 2 0 0-60 61-90 91-120 121-150 151-180 >180 Door-to-balloon time (minutes)
Reperfusion I I IIa IIb III IIa IIb III STEMI patients presenting to a hospital with PCI capability should be treated with primary PCI within 90 minutes of first medical contact. Modified recommendation STEMI patients presenting to a hospital without PCI capability and who cannot be transferred to a PCI center for intervention within 90 minutes of first medical contact should be treated with fibrinolytic therapy within 30 minutes of hospital presentation, unless contraindicated. Modified recommendation
Meta-Analysis of 17 Facilitated PCI Trials* Event Facilitated PCI (%) PCI (%) P Death 5.0 3.0.04 Reinfarction 3.0 2.0.006 Urgent TVR 4.0 1.0.010 Major bleeding 7.0 5.0.010 Stroke 1.1 0.3.0008 *Includes 9 GP IIb/IIIa inhibitor trials (n=1148); 6 thrombolytic therapy trials (n=2957); 2 combination therapy trials (n=399) Keeley EC. Lancet. 2006;367:579-588. STRIVE TM
600 patients randomized
Facilitated PCI I IIa IIb III Facilitated PCI using regimens other than full-dose fibrinolytic therapy might be considered as reperfusion strategy when the following are present: Patients at high risk PCI is not immediately available within 90 minutes Bleeding risk is low Younger age Absence of poorly controlled hypertension Normal body weight Modified recommendation I IIa IIb III A planned reperfusion strategy using full-dose fibrinolytic therapy followed by immediate PCI may be harmful. Modified recommendation
Four-year cumulative event rates in OAT Outcome PCI (%) Medical (%) HR 95% CI p Death, MI, HF 17.2 15.6 1.16 0.92 1.45 0.20 All MI 7.0 5.3 1.36 0.92 2.00 0.13 Nonfatal MI 6.9 5.0 1.44 0.96 2.16 0.08 NYHA class 4 HF 4.4 4.5 0.98 0.64 1.49 0.92 Death 9.1 9.4 1.03 0.77 1.40 0.83 2,166 STEMI patients randomized 3 to 28 days after AMI Hochman JS et al. N Engl J Med 2006;
TOSCA-2 2 Trial: Primary Endpoint 5% 4% 3% 2% 1% 0% Change in LV Ejection Fraction at One Year (% increase) n = 195 p=0.47 n = 196 4.2% 3.5% PCI Medical Therapy ( 83% patency at 1 yr ) ( 23% patency at 1 yr ) Change in LV ejection fraction (LVEF) at one year did not differ between the PCI and medical therapy group (4.2% increase with PCI vs. 3.5% increase with medical therapy, p=0.47). www. Clinical trial results.org Dzavik, V et al. Presented Circulation; AHA Nov. 2006 2006
PCI After Successful Fibrinolysis or for Patients Not Undergoing Primary Reperfusion I IIa IIb III PCI of a hemodynamically significant stenosis in a patent infarct artery greater than 24 hours after STEMI may be considered as part of an invasive strategy. Modified recommendation I IIa IIb III PCI of a totally occluded infarct artery greater than 24 hours after STEMI is not recommended in asymptomatic patients with one- or two-vessel disease if they are hemodynamically stable and do not have evidence of severe ischemia. New recommendation
Meta-Analysislsis:: Stenting vs Balloon for STEMI(13RCT s; n=6921) 12- month MORTALITY STUDY WITHOUT ABCIXIMAB I II STENTING BALLOON n/n (%) n/n (%) OR (fixed) 95% CI Weight % OR 95% CI P value CADILLAC 17/512 (3.3%) 28/518 (5.4%) 16.47 0.60 [0.32, 1.11] 1.0 FRESCO 1/75 (1.3%) 4/75 (5.3%) 2.42 0.24 [0.03, 2.20] 0.36 Jacksch et al 5/231 (2.2%) 7/231 (3.0%) 4.19 0.71 [0.22, 2.26] 0.56 PAMI 26/452 (5.8%) 14/448 (3.1%) 8.11 1.89 [0.97, 3.67] 0.056 PASTA 3/67 (4.5%) 6/69 (8.7%) 3.46 0.49 [0.12, 2.05] 0.49 PSAAMI 4/44 (9.1%) 8/44 (18.2%) 4.45 0.45 [0.12, 1.62] 0.35 STENTIM-2 3/101 (3.0%) 2/110 (1.8%) 1.14 1.65 [0.27, 10.1] 0.58 ZWOLLE-5 3/112 (2.7%) 4/115 (3.5%) 2.35 0.76 [0.17, 3.49] 1.0 ZWOLLE-6 47/785 (6.0%) 45/763 (5.9%) 26.26 1.02 [0.67, 1.55] 0.94 WITHI ABCIXIMAB II STOPAMI-3 25/305 (8.2%) 28/306 (9.2%) 15.71 0.89 [0.50, 1.56] 0.67 STOPAMI-4 7/90 (7.8%) 11/91 (12.1%) 6.21 0.61 [0.23, 1.66] 0.33 CADILLAC 28/524 (5.3%) 16/528 (3.0%) 9.23 1.81 [0.97, 3.38] 0.061 ABCIXIMAB 60/919 (6.5%) 55/925 (5.9%) 31.25 1.10 [0.76, 1.61] 0.6 CONTROL 109/2379 (4.6%) 118/2373 (5.0%) 68.75 0.92 [0.70, 1.20] 0.5 TOTAL (95% CI) 169/3298 (5.1%) 173/3298 (5.2%) 100.00 0.97 [0.78, 1.21] 0.81 De De Luca, Luca, Suryapranatarrt, Suryapranatarrt et al. et al. JACC 2006t l. 0.1 0.2 0.5 1 2 5 10 I JACC 2006l. STENT BETTER BALLOON BETTER STENT BETTER BALLOON BETTER
Randomized Trials of DES vs BMS for AMI TVR Odds Ratio ti P (95% C.I.) Value Strategy 0.29 (0.11, 0.11) 0.0091. Typhoon 0.38 (0.22, 0.66) 0.0004. SESAMII 0.35 (0.15, 0.81) 0.011. Passion (TLR)i () 0.70 (0.36, 1.34) 0.28. Combinedi 0.43 (0.30, 0.61) <0.0001 0 0.2 0.4 0.6 0.8 1 1.2 1.4
Randomized Trials of DES vs BMS for AMI Odds Ratio P (95% C.I.) Value Death Strategy 0.88 (0.30, 2.53) 0.81 Typhoon 1.01 (0.37, 271) 0.99 SESAMI 0.25 (0.03, 2.22) 0.37 Passion 0.70 (0.35, 1.42) 0.32 Combined 0.75 (0.46, 1.22) 0.24 MI Strategy 0.74 (0.25, 2.23) 0.59 Typhoon 0.80 (0.21, 3.01) 1.00 SESAMI Passion 0.85 (0.26, 2.28) 0.79 Combined 0.80 (0.40, 1.58) 0.51 Stent Thrombosis Strategy 0.25 (0.01, 5.56) 0.34 Typhoon 0.93 (0.42, 2.06) 0.85 Passion 1.02 (0.20, 5.11) 1.00 Combined 0.86 (0.47, 1.56) 0.62 0 1 2 3 4 5 6 Grines,C. AHA Nov 2007
GRACE Registry Mortality Rates Comparing 569 Patients Receiving DES with 1,729 Patients Receiving BMS During PCI for Acute Myocardial Infarction End point Hazard Ratio Death, 0 180 d 0.988 Death, 180 730 d 4.67 Death, 180 730 d, 6.02 adjusted for GRACE risk score* Death, 180 730 d, adjusted for 5.81 GRACE risk score and propensity* STRIVE TM
Effect of Clopidogrel on 24-Month Events in Patients Who Were Event-Free at 6 Months* 24-Month Events Eisenstein EL et al. JAMA. 2007;297:159-68. With Without Clopidogrel Clopidogrel Drug-Eluting Stent (DES) Patients (n) 637 579 Difference (95% CI) P Value Death 2.0% 5.3% -3.3% (-6.3%( to -0.3%) 0.03 Death or MI 3.1% 7.2% -4.1% (-7.6%( to -0.6%) 0.02 Bare-Metal Stent (BMS) Patients (n) 417 1,976 Death 3.7% 4.5% -0.7% (-2.9%( to 1.4%) 0.50 Death or MI 5.5% 6.0% -0.5% (-3.2%( to 2.2%) 0.70 *Exclusions: DES (Death 62, nonfatal MI 18, revasc 76, meds not reported 129 (total 285/1502) BMS (Death 123, nonfatal MI 94, revasc 289, meds not reported 266 (total 772/3165)
Harmonizing Outcomes with Revascularization and Stents in AMI 3400* pts with STEMI with symptom onset 12 hours Aspirin, thienopyridine UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) R 1:1 Bivalirudin monotherapy (± provisional GP IIb/IIIa) Emergent angiography, followed by triage to CABG Primary PCI Medical Rx 3000 pts eligible for stent randomization R 1:3 Bare metal stent TAXUS paclitaxel-eluting eluting stent *To rand 3000 stent pts Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years
ExTRACT-TIMI 25: Protocol Design STEMI < 6 h Lytic eligible ASA Lytic choice by MD (TNK, tpa, rpa, SK) Enoxaparin (N=10,256) < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC) 75 y: No bolus SC 0.75 mg / kg q 12 h (Hosp DC) CrCl < 30: 1.0 mg / kg q 24 h Double-blind, double-dummy UFH (N=10,223) 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Duration: at least 48 h Cont d at MD discretion Day 30 1 Efficacy End Point: Death or Nonfatal MI 1 Safety End Point: TIMI Major Hemorrhage ExTRACT=Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction. Antman EM et al. N Engl J Med. 2006;354:1477-1488. Adapted with permission from http://www.clinicaltrialresults.com. STRIVE TM
% 12 9 6 3 Main Results From ExTRACT TIMI 25 Primary End Point: Death or nonfatal re-mi by 30 days RR=0.83 P<.001 UFH ENOX 12.0 9.9 % Main Secondary End Point: Death, nonfatal re-mi, or urgent revascularization by 30 days RR=0.81 P<.001 UFH ENOX 0 0 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Days Days 15 12 9 6 3 RR=0.88 P=.02 14.5 11.7 Major bleeding at 30 days: 1.4% with UFH vs 2.1% with enoxaparin (P<.001) ICH: 0.7% for UFH vs 0.8% for enoxaparin (P=.14) Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354:1477-1488. STRIVE TM
ExTRACT-TIMI 25 PCI Cohort: Primary End point Death or Nonfatal MI by 30 days Death or MI (%) 15 10 2,404 Underwent PCI by 30 days 24.2% RR 0.77 P=0.001 EVENT ENOX UFH RR 5 2,272 Underwent PCI by 30 days 22.8% 0 0 5 10 15 20 25 30 Days UFH 13.8% ENOX 10.7% TIMI Major Bleed 1.4% 1.6% 0.87 (0.55-1.39).56 TIMI Minor Bleed 3.3% 2.4% 1.34 (0.95-1.88).09 ICH 0.2% 0.4% 0.42 (0.13-1.35).18 Stroke 0.3% 0.9% 0.30 (0.12-0.75).006 P Gibson M. Presented at World Congress of Cardiology; September 4, 2006; Barcelona, Spain. Adapted with permission from www.clinicaltrialresults.org. STRIVE TM
Anticoagulants as Ancillary Therapy I IIa IIb III Patients undergoing reperfusion with fibrinolytics should receive anticoagulant therapy for a minimum of 48 hours, and preferably for the duration of the index hospitalization, up to 8 days. New Recommendation I IIa IIb III Regimens other than UFH are recommended if therapy is given for more than 48 hours because of risk of heparin-induced induced thrombocytopenia. New Recommendation Regimens with established efficacy include: UFH, enoxaparin, fondaparinux (see full text Update for dosing recommendations)
CLARITY TIMI 28: Study Design Double-blind, randomized, placebo-controlled trial in 3491 patients, aged 18-75 yrs, with STEMI <12 hours Fibrinolytic, ASA, Heparin Randomized Study Drug Open-label clopidogrel per MD in both groups Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) 30-day clinical follow-up Placebo Primary end point: Occluded artery (TIMI flow grade 0/1) or death/mi by time of angio Sabatine MS, et al. N Engl J Med. 2005;352:1179-1189. STRIVE TM
CLARITY TIMI 28: End Points Primary End Point Occluded Artery (or Death/MI Through Angio/HD) CV Death, MI, RI Urg Revasc Occluded Artery or Death/MI (%) 25 20 15 10 5 0 36% Odds Reduction 15.0 21.7 n=1752 n=1739 Clopidogrel Placebo Endpoint (%) 15 10 5 0 Placebo 0 5 10 15 20 25 30 Days Clopidogrel Odds Ratio: 0.80 (95% CI, 0.65-0.97) P=.03 20% Sabatine MS, et al. N Engl J Med. 2005;352:1179-1189. Note: No increase in major or minor bleeding or ICH seen STRIVE TM
COMMIT: Effect of Clopidogrel on Death, Re-MI, or Stroke Placebo + ASA: 2311 events (10.1%) Placebo + ASA: 1846 deaths (8.1%) 9 8 7 Clopidogrel + ASA: 2125 events (9.3%) 7 6 Clopidogrel + ASA: 1728 deaths (7.5%) Event (%) 6 5 4 3 2 9% (SE3) relative risk reduction (P=.002) Mortality (%) 5 4 3 2 7% (SE3) relative risk reduction (P=.03) 1 1 0 0 0 7 14 21 28 0 7 14 21 28 Days Since Randomization (up to 28 days) Days Since Randomization (up to 28 days) COMMIT Collaborative Group. Lancet. 2005;366:1607-1621. Note: No increase in major bleeding or ICH was seen STRIVE TM
Clopidogrel I I I IIa IIb III IIa IIb III IIa IIb III For all post-pci patients receiving a DES, clopidogrel 75 mg daily should be given for at least 12 months, if not at high risk of bleeding. b For post-pci patients receiving a BMS, it should be given for a minimum of 1 month and ideally up to 12 months (unless patient is at increased risk of bleeding). Modified recommendation For all STEMI patients not undergoing a stent placement (medical therapy alone or PTCA without stenting), treatment with clopidogrel should continue for at least 14 days. New recommendation Long-term maintenance therapy (e.g. 1 year) with clopidogrel is reasonable in STEMI patients, regardless of whether or not they undergo reperfusion therapies. New recommendation
COMMIT: Effects of METOPROLOL on Death in hospital Placebo: 1798 deaths (7.8%) Metoprolol: 1776 deaths (7.7%) % dead 1% (SE 3) relative risk reduction (2P=0.7) Days since randomisation
COMMIT: Effects of METOPROLOL on Death by attributed cause(s) Cause(s) Metoprolol Placebo Odds ratio & 95% CI (22,927) (22,922) Metop. better Placebo better Arrhythmia 388 (1.7%) 498 (2.2%) 22% SE 6 Shock 496 (2.2%) 384 (1.7%) -29% SE 8 Other causes 892 (3.9%) 916 (4.0%) 3% SE 5 ANY DEATH 1776 (7.7%) 1798 (7.8%) 1% SE 3 (2P > 0.1; NS) 0.4 0.7 1.0 1.3 1.6 1.9
Effects of iv then oral β-blocker on reinfarction in 3 major trials of acute MI Trial ß-blocker Control Odds ratio & 95% CI (33,841) (33,813) ß-blocker better Control better MIAMI 85 (3.0%) 111 (3.8%) ISIS-1 148 (1.8%) 161 (2.0%) COMMIT 467 (2.0%) 568 (2.5%) OVERALL 700 (2.1%) 840 (2.5%) 17% SE 5 (2P = 0.0003) 0.4 0.6 0.8 1.0 1.2 1.4 1.6
Beta-Blockers Blockers I IIa IIb III Oral beta-blocker blocker therapy should be initiated in the first 24 hours for patients who do not have the following: Signs of heart failure Evidence of low output state Increased risk for cardiogenic shock Age >70 years Systolic blood pressure <120 mm Hg Sinus tachycardia (heart rate >110 or < 60 bpm) Increased time since onset of symptoms of STEMI Relative contraindications to beta-blockade blockade PR interval >0.24 seconds second- or third-degree degree heart block active asthma or reactive airway disease Modified recommendation
Beta-Blockers Blockers I IIa IIb III It is reasonable to administer an IV beta-blocker blocker at the time of STEMI presentation to patients who are hypertensive and who do not have any of the following: Signs of heart failure Evidence of low output state Increased risk for cardiogenic shock Other relative contraindications to beta-blockade blockade (text modified) No change in recommendation (text modified) I IIa IIb III IV beta blockers should not be administered to patients who have any of the following: Signs of heart failure Evidence of low output state Increased risk of cardiogenic shock Other relative contraindications to beta-blockade blockade New recommendation
: Primary Endpoints EPHESUS Trial: Primary Endpoints n = 6,632 AMI with HF and LVEF< 40 20% 15% All-cause Mortality Mean FU 16 mos RR 0.85 40% p=0.008 16.7% 14.4% 30% CV Death or Hospitalization RR 0.83 p=0.005 30.0% 26.7% 10% 20% 5% 10% 0% 0% Eplerenone Placebo Note: www. RR Clinical 0.69 trial (CI 0.54-0.89), results.org p=.004 at 30 days Eplerenone Placebo N Engl J Med 2003;348:1309-21
Kaplan-Meier estimates of the rate of all-cause mortality at 30 days in EPHESUS 37% RRR of Sudden Death Note: All the benefit was seen in patients randomized between 3 and 7 days. No benefit was seen in 30d mortality if randomized between 8 and 14 d. Zannad, F. ACC Mar 2007 Pitt, B. et al. J Am Coll Cardiol 2005;46:425-431
Aldosterone Blockade Use of aldosterone blockade in post-mi patients without significant renal dysfunction or hyperkalemia is recommended in patients who: I IIa IIb III are already receiving therapeutic doses of ACE inhibitor and beta blocker an have a LVEF of less than or equal to 40% have either diabetes or HF Modified recommendation
Managing STEMI in 2007: Summary Acute therapy focuses on reperfusion and antithrombotic therapy PCI generally preferred over fibrinolysis when a skilled PCI lab is available with surgical backup and door-to-balloon time is <90 min. Also, in all patients with symptoms for > 3 hours. Fibrinolysis generally preferred when invasive strategy is not an option or when delay to PCI is anticipated (>90 min door-toballoon) in patients presenting within 3 hours of onset. Current ACC/AHA STEMI guidelines recommend IV UFH as ancillary therapy to reperfusion therapy (Class I) ExTRACT-TIMI 25 showed enoxaparin superior to current standard of UFH as the antithrombin to support fibrinolysis. An increase in bleeding with enoxaparin vs UFH is outweighed by an overall net clinical benefit in favor of enoxaparin Clopidogrel on top of aspirin results in significant further improvement in the reperfusion of STEMI patients either with fibrinolysis (CLARITY/COMMIT) or with PCI. STRIVE TM
Summary: STEMI (continued) Facilitated PCI with full dose lytic worse outcome Rescue PCI benefit for failed lysis Bivalirudin appears superior to UHF + GPiib/iiia for PCI (HORIZON trial) Recanalization of a total residual occlusion after fibrinolysis in an asymptomatic patients is unwarranted Fondaparinux: D/MI vs placebo; = D/MI vs UFH; no difference in bleeding. However, increase in guiding catheter thrombosis At present, use of a BMS seems preferable to DES. Diabetic patient may be an exception because of high restenosis rate Prasugrel not yet ready for prime time Start Eplerenone on top of ACEI and BB between day 3 and 7 if early HF symptoms occured and LVEF <40 STRIVE TM